Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N‐terminally modified peptide aldehydes and their antitumor activity

Abstract

The conversion of primary structures of novel, highly selective and sensitive, internally quenched peptide substrates of the human 20S proteasome into peptide aldehydes is presented. Such covalent and reversible inhibitors differ in their primary structures and chemical moieties attached to their N‐terminal amino group. Inhibitory potency is primarily tested against proteolytic subunits of human constitutive 20S proteasome (β1c, β2c, and β5c subunits), but in some cases, also against 20S immunoproteasome β5i. Most of the peptide aldehydes act nonspecifically and bind equipotently to the corresponding proteolytic subunits of both forms of proteasome (β5c and β5i). Two inhibitors are 2.7‐times more specific for immunoproteasome over its constitutive counterpart. The antitumor activity of the selected inhibitors and MG132 (used here as the reference) is analyzed using MTT assay against nonmalignant human fetal osteoblastic hFOB 1.19, malignant human osteosarcoma MG‐63, human pancreatic cancer MiaPaCa‐2, and human acute leukemia Jurkat T cell lines. All inhibitors tested are able to decrease cell viability in a concentration‐dependent manner. One of the peptide aldehydes exerted stronger, as compared to the MG132, activity against human glioblastoma cell line U87‐MG. Moreover, its combination with dinaciclib, which is a novel, potent inhibitor of cyclin‐dependent kinases, reduces cellular metabolic activity more potently as compared to either proteasome inhibitor or dinaciclib alone.

Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction

“…The peptidomimetic inhibitors such as carfilzomib and ONX-0914 tend to occupy all four subpockets (S1–S4) meant for accommodating P1–P4 residues. In contrast, bortezomib and IPSI-001 occupied three (S1–S3) and two (S1 and S2) subpockets, respectively [ 52 ]. Our compound BrPQ5 , when compared to reported inhibitors, is quite small and could interact only with residues lining the S1 subpocket in all three cases (beta-5: S1 hydrophobic, beta-2: S1: acidic, and beta-1: S1 basic).…”